The type I Melanoma Antigen GEnes (MAGE) are expressed in a broad range of human cancers, but their normal expression is tightly restricted to developing germ cells and trophoblastic tissue. We discovered that MAGE-A3 and CT7 (MAGE-C1) are commonly expressed in multiple myeloma, an incurable blood cancer, and their expression was correlated with progression of disease and proliferation. These type I MAGE inhibit p53- dependent and independent mechanisms apoptosis through ubiquitin ligase activity and confer resistance to chemotherapy-induced apoptosis in myeloma cells. Type I MAGE are a novel class of therapeutic targets in cancer, and understanding the mechanisms by which they antagonize apoptosis is critical to the development of pharmaceutical agents them. This investigation will use an innovative structural biology approach exploiting a unique feature, conformational plasticity of the MAGE Homology Domain, to perform in silico screening for MAGE-specific small molecules, then perform detailed biochemical analysis on this reduced sets of candidates to demonstrate direct binding to the MHD and induction of apoptosis. MAGE-directed therapy may target myeloma cells with an unprecedented degree of precision because of their tightly-restricted expression in normal tissues. These agents may either directly induce apoptosis or make myeloma cells more vulnerable to chemotherapy-induced apoptosis. Combination therapy with MAGE inhibitors may increase response rates and prolong survival in this currently incurable disease. These novel targeted therapies may have broader application in other cancers that express MAGE, including skin, lung, breast, and prostate cancers, some of the leading causes of cancer death.